WO2002036586A1 - Antagonistes des canaux calciques de type n pour le traitement de la douleur - Google Patents

Antagonistes des canaux calciques de type n pour le traitement de la douleur Download PDF

Info

Publication number
WO2002036586A1
WO2002036586A1 PCT/SE2001/002388 SE0102388W WO0236586A1 WO 2002036586 A1 WO2002036586 A1 WO 2002036586A1 SE 0102388 W SE0102388 W SE 0102388W WO 0236586 A1 WO0236586 A1 WO 0236586A1
Authority
WO
WIPO (PCT)
Prior art keywords
structural diagram
compound
alkyl
compound according
pain
Prior art date
Application number
PCT/SE2001/002388
Other languages
English (en)
Inventor
Bipinchandra Chaudhari
Marc Chapdelaine
Greg Hostetler
Lucius Kemp
John Mccauley
Original Assignee
Astrazeneca Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab
Priority to EP01981239A priority Critical patent/EP1339706B1/fr
Priority to AU2002212894A priority patent/AU2002212894A1/en
Priority to JP2002539345A priority patent/JP2004513125A/ja
Priority to US10/415,785 priority patent/US6815447B2/en
Priority to DE60118956T priority patent/DE60118956T2/de
Publication of WO2002036586A1 publication Critical patent/WO2002036586A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • This invention relates to compounds and methods for the treatment or prevention of pain or nociception.
  • the level of stimulation at which pain is perceived is referred to as the "pain threshold".
  • the pain threshold is raised, for instance, by the administration of an analgesic drug, a greater intensity or more prolonged stimulus is required before pain is experienced.
  • Analgesics are a class of pharmaceutical agent which, following administration to a patient in need of such treatment, relieve pain without loss of consciousness. This is in contrast to other pain-relieving drugs, for example, general anaesthetics which obtund pain by producing a hiatus in consciousness, or local anaesthetics which block transmission in peripheral nerve fibres thereby preventing pain.
  • Tachykinin antagonists have been reported to induce antinociception in animals, which is believed to be analogous to analgesia in man (for review see Maggi et al, J. Auton. Pharmacol. (1993) 13, 23-93).
  • non-peptide NK-1 receptor antagonists have been shown to produce such analgesia, thus, for example, in classical tests of chemo-nociception (phenylbenzoquinone-induced writhing and formalin test) the NK-1 receptor antagonist RP 67,580 produced analgesia with potency comparable to that of morphine (Garret et al, Proc. Natl. Acad. Sci. USA (1993) 88, 10208-10212).
  • Opioid analgesics are a well-established class of analgesic agents. These compounds are generally accepted to include, in a generic sense, all drugs, natural or synthetic, with morphine-like actions.
  • the synthetic and semi-synthetic opioid analgesics are derivatives of five chemical classes of compound: phenanthrenes; phenylheptylamines; phenylpiperidines; morphinans; and benzomorphans. Pharmacologically these compounds have diverse activities, thus some are strong agonists at the opioid receptors (e.g. morphine); others are moderate to mild agonists (e.g. codeine); still others exhibit mixed agonist-antagonist activity (e.g.
  • nalbuphine and yet others are partial agonists (e.g. nalorphine).
  • an opioid partial agonist such as nalorphine, (the N-alkyl analogue of morphine) will antagonise the analgesic effects of morphine, when given alone it can be a potent analgesic in its own right.
  • opioid analgesics morphine remains the most widely used and is a suitable archetype compound.
  • morphine also has a number of drawbacks including respiratory depression, decreased gastrointestinal motility (resulting in constipation) and, in some individuals, nausea and vomiting may occur. Another characteristic is the development of tolerance and physical dependence which may limit the clinical use of such compounds.
  • Anti-inflammatory compounds directed at blocking or reducing synovial inflammation, and thereby improving function, and analgesics directed to reducing pain, are presently the primary method of treating the rheumatoid diseases and arthritis.
  • Aspirin and other salicylate compounds are frequently used in treatment to interrupt amplification of the inflammatory process and temporarily relieve the pain.
  • Other drug compounds used for these purposes include phenylpropionic acid derivatives such as Ibuprofen and Naproxin, S lindac, phenyl butazone, corticosteroids, antimalarials such as chloroquine and hydroxychloroquine sulfate, arid fenemates.
  • Calcium channels are membrane-spanning, multi-subunit proteins that allow controlled entry of Ca " " " ions into cells from the extracellular fluid. Such channels are found throughout the animal kingdom, and have been identified in bacterial, fungal and plant cells. Commonly, calcium channels are voltage dependent. In such channels, the "opening" allows an initial influx of Ca** ' ions into the cells which lowers the potential difference between the inside of the cell bearing the channel and the extracellular medium bathing the cell. The rate . of influx of Ca "1"1' ions into the cell depends on this potential difference.
  • All “excitable” cells in animals such as neurons of the central nervous system (“CNS”), peripheral nerve cells, and muscle cells, including those of skeletal muscles, cardiac muscles, and venous and arterial smooth muscles, have voltage-dependent calcium channels.
  • Calcium channels are physiologically important because the channels have a central role in regulating intracellular Ca " - ions levels. These levels are important for cell viability and function.
  • intracellular Ca* "1" ion concentrations are implicated in a number of vital processes in animals, such as neurotransmitter release, muscle contraction, pacemaker activity, and secretion of hormones. It is believed that calcium channels are relevant in certain disease states.
  • a number of compounds useful in treating various cardiovascular diseases in animals, including humans, are thought to exert their beneficial effects by modulating functions of voltage-dependent calcium channels present in cardiac and/or vascular smooth muscle. Many of these compounds bind to calcium channels and block, or reduce the rate of, influx of Ca* ions into the cells in response to depolarization of the cell membrane.
  • a synthetic version of ⁇ -conotoxin MNIIA, a 25-amino acid peptide derived from the venom of the piscivorous marine snail, Conus magus has been used intrathecally in humans and has ⁇ 85% success rate for the treatment of pain with a greater potency than morphine.
  • the present invention provides compounds having selective action at N- type calcium channels that are useful for the treatment of pain.
  • R is NE E where E is selected from hydrogen and methyl and E is selected from hydrogen, C 1-4 alkyl and
  • R 2 is selected from E 3 and E 4 , wherein:
  • E 3 is selected from C 1-6 alkyl, C 1-4 alkoxy and C 1-6 alkoxyC 1-4 alkyl; and E 4 is phenyl substituted with a moiety selected from halogen, C 1- alkyl, C ]-4 alkoxy, perfluoroC 1-2 alkyl and C -7 cycloalkyl;
  • R is selected from E and E , wherein:
  • E 5 is selected from NH 2 , perfluoro ⁇ alkyl, C 1-6 alkyl, C 1-6 alkoxyC 1- alkyl, phenylC ⁇ -2 alkoxy and phenoxyC ]-2 alkyl; and E 6 is phenyl substituted at one or two positions with moieties independently selected from halogen, cyano, perfluoroC 1-2 alkyl, phenylC 1-2 alkoxy, phenoxyC ⁇ -2 alkyl, C ⁇ -6 alkoxyC 1-4 alkyl.
  • R 1 is NE'E 2 where E 1 is hydrogen and E 2 is selected from hydrogen, methyl and benzyl;
  • R 2 is selected from E 3 and E 4 , wherein:
  • E is selected from methyl, pentyl, propoxymethyl
  • E 4 is phenyl substituted with a moiety selected from fluoro, chloro, methyl, methoxy, trifluoromethyl and cyclohexyl;
  • R 3 is selected from E 5 and E 6 , wherein:
  • E 5 is selected from methyl, pentyl, trifluoromethyl, propoxymethyl, benzyloxy and phenyloxymethyl;
  • E 6 is phenyl substituted at one or two positions with moieties independently selected from chloro, fluoro, butyl, trifluoromethyl, methoxy, ethoxy, benzyloxy, phenoxymethyl, propoxymethyl and cyano.
  • the invention comprises a method for using compounds according to structural diagram I for the treatment of pain, said method comprising administering a pain- ameliorating effective amount of any such compound.
  • One embodiment of the method of the invention comprises administering a pain- ameliorating effective amount of a compound in accordance with structural diagram I to a subject in need of treatment for acute, persistent or neuropathic pain.
  • the invention comprises methods for making compounds in accord with structural diagram I.
  • the invention comprises pharmaceutical compositions comprising compounds in accord with structural diagram I together with excipients, diluents or stabilisers, as further disclosed herein, useful for the treatment of acute, persistent and neuropathic pain.
  • Suitable pharmaceutically-acceptable salts of compounds of the invention include acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, tris(hydroxymethyl)aminomethane, maleate and salts formed with phosphoric and sulphuric acid.
  • acid addition salts such as methanesulphonate, fumarate, hydrochloride, hydrobromide, citrate, tris(hydroxymethyl)aminomethane, maleate and salts formed with phosphoric and sulphuric acid.
  • Another aspect of the invention provides processes for making compounds of the invention.
  • compounds of the invention were prepared by preparing chloro- pyrimidine or triflate-pyrimidine precursors from hydroxy-pyrimidine precursors, and reacting said chloro-pyrimidine or triflate-pyrimidine precursors with quinoline precursors to . form pyrimidyl-quinoline compounds of the invention.
  • Hydroxy-pyrimidine precursors were prepared by reacting a 3-substituted-3-oxo- pr ⁇ pionic ethyl ester with guanidine hydrochloride in N-dimethylformamide in the presence of sodium hydride and activated 5 A molecular seives.
  • Chloro-pyrimidine precursors were prepared by chlorinating a hydroxy-pyrimidine compound according to structural diagram II by refluxing with phosphoryloxychloride and phosphorus pentachloride to form a compound in according to structural diagram III,
  • Triflate-pyrimidine precursors were prepared by reacting a hydroxy-pyrimidine compound according to structural diagram II by heating with N-phenyl trifluoromethane sulfonamide, triethylamine and dry N-methyl-2-pyrolidinone to form a compound in according to structural diagram IV,
  • Novel precursor quinolines were prepared according to the following process: dl) preparing novel 3-substituted-3-oxo-propionic acid ethyl esters ( ⁇ -keto esters) according to structural diagram V, as follows:
  • a pharmaceutical composition which contains a compound of the structural diagram I as defined herein or a pharmaceutically-acceptable salt thereof, in association with a pharmaceutically-acceptable additive such as an excipient or carrier.
  • Suitable pharmaceutical compositions that contain a compound of the invention may be administered in conventional ways, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration, or by inhalation.
  • a compound of the invention may be formulated by means known in the art in the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • a preferred route of administration is orally by tablet or capsule.
  • a pharmaceutical composition of this invention may also contain one or more other pharmacologically-active agents.
  • a pharmaceutical composition comprising a compound of this invention may be co-administered simultaneously or sequentially with one or more other compatible pharmacologically-active agents.
  • compositions of this invention will normally be administered so that a pain-ameliorating effective daily dose is received by the subject.
  • the daily dose may be giyen in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • a preferred dosage regime is once daily.
  • a yet further embodiment of the invention provide the use of a compound of the structural diagram I, or a pharmaceutically-acceptable salt thereof, in the manufacture of a medicament useful for binding to N-type calcium channels in a warm-blooded animal such as a human being.
  • Still another embodiment of the invention provides a method of binding a compound of the invention to N-type calcium channels of a warm-blooded animal, such as a human being, in need of treatment for pain, which method comprises administering to said animal an -effective amount of a compound of structural diagram I or a pharmaceutically-acceptable salt thereof.
  • a further aspect of the present invention provides a pharmaceutical composition which includes a compound of the present invention as defined herein or a pharmaceutically- acceptable salt thereof, in association with a pharmaceutically-acceptable additive such as an excipient or a carrier.
  • a pharmaceutically-acceptable additive such as an excipient or a carrier.
  • a still further aspect of the present invention is a method of treatment of the human or animal body that includes the administration of a compound of the present invention or a pharmaceutically-acceptable salt thereof.
  • halo or halogen means fluoro, chloro, bromo or iodo; when substituents herein are stated to be “selected from” or “independently selected from” a group of moieties, it is to be understood that included compounds are those where all substituents are the same and compounds where each substituent is different; when used herein the term “alkyl,” as in for example C 1-6 alkyl, unless otherwise defmed, includes both straight and branched chain alkyl groups.
  • references to individual alkyl groups such as "propyl” mean the normal, straight chain form, that is, n-propyl; when used herein, a term such as "C ⁇ aU yl” means alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms and collective groups such as C 1-4 alkyl and includes straight and branched moieties such as methyl, ethyl, wo-propyl and t-butyl, similarly, a term such as "C 1-3 alkoxy” includes particular moieties such as methoxy, ethoxy and propoxy, and terms used herein that are not otherwise defined are intended to have their conventionally-understood meaning.
  • DMSO dimethylsulfoxide
  • CDC1 3 is deuterated chloroform
  • FAB fast atom bombardment
  • m/s is mass spectroscopy or mass spectral
  • NMR Nuclear Magnetic Resonance
  • NMP is N-methylpyrrolidinone
  • THF is tetrahydrofuran.
  • N-channel FLIPR Fluorescent Laser Imaging Plate Reader
  • the methods described herein provide a reliable FLIPR-based readout of the efficacy and potency with which test compounds inhibit calcium flux through the N-type calcium channel expressed in its native form in a human-derived neuroblastoma cell line differentiated chemically to a neuronal phenotype.
  • the degree to which a compound at a particular concentration inhibited the N-channel calcium flux was determined by comparing the amplitude of peak calcium increase in the presence of the compound to a control 80 mM K + stimulus in wells without compound.
  • IMR32 An immortalized cell line, IMR32, derived from human neuroblastoma cells obtained from the ATCC (product #CCL-127) was used for all experiments.
  • Cells were grown in T75 flasks containing Eagle's minimum essential medium (MEM) w/ Earle's salts and non- essential amino acids without glutamine (Cat.#SLM-034-B, Specialty Media, Philipsburg, ⁇ J), 10% FBS and 1 % glutamine.
  • ' Cells were grown to ⁇ 70-80% confluency (by visual ' microscopic estimation) before sub-culturing.
  • cultures were split at a ratio of 1 :3 - 1 :4 by creating a cell suspension by trituration, and pipetting a volume of the cell suspension sufficient to yield this final ratio into new flasks containing ⁇ 20 mL of fresh media. Sub-culturing was generally performed two times per week. For preparation of 96 well plates (black-walled; Cat # 3603, Costar Co., Cambridge, MA), a T75 flask containing cells of desired confluency was brought up to 120 mL volume with media. Cells were then freed by trituration, and the cell suspension was plated into 12-96 well plates to yield final well volume of 100 ⁇ L.
  • Cells were induced to differentiate in a differentiation medium consisting of: MEM, 10% FBS, 1% glutamine, l ⁇ M 2-butyl-cAMP (49.1 mg/100 mL media (Cat. # D-0627, Sigma Corp., St Louis, MO), and 2.5 mM bromo-deoxy-uridine (stock: 30.7 mg/10 mL media, 25 mL of above stock/100 mL media; Sigma Cat .# B-9285).
  • the cells were treated with differentiation media (by complete medium change) 2 days after an initial plating in 96 well plates. Confluency at this time was ⁇ 40%. A complete medium change with freshly prepared differentiating medium was subsequently performed every 2-3 days. Cells were exposed to these differentiation conditions for 6 to 11 days before being used in FLIPR experiments.
  • Buffer A (first wash buffer): Krebs-Ringer-HEPES (KRH) buffer: NaCl: 125, KC1: 5, MgSO 4 : 1.2, KH 2 PO 4 : 1.2, CaCl 2 2H 2 O: 2, Glucose: 6, HEPES: 25, pH: 7.4 (pH adjusted with NaOH)
  • Buffer B (dye loading buffer): KRH buffer with 2.5 ⁇ M probenicid: same as buffer
  • Probenecid (Cat. # P-8761, Sigma Chemical Co., St. Louis, MO) made as a stock solution at 250 mM.
  • Buffer C (dye washout buffer): KRH buffer with 0 mM K + and 2.5 ⁇ M probenicid: NaCl: 130, MgSO 4 :1.2, NaH 2 PO 4 : 1.2, CaCl 2 2H 2 O: 2, Glucose: 6, HEPES: 25, pH: 7.4 (pH adjusted with NaOH).
  • Buffer D compound dilution buffer
  • Buffer C Buffer C with 0.1% w/v bovine serum albumin (BSA; Sigma).
  • Nitrendipine (RBI Chemicals, Natick, MA): Stock: 10 mM in DMSO; Pipetting solution: 9 ⁇ M; pipette 20 ⁇ L into 120 ⁇ L volume in well for final well concentration: 1 ⁇ M.
  • w-Conotoxin MNIIA (Cat. # H-8210; Bachem Inc., Torrance, CA): Stock: 1 mM in HPLC grade H 2 0 with 0.1% BSA; Pipetting solution: 4.5 ⁇ M; pipette 20 ⁇ l into 140 ⁇ l volume in well for final well concentration: 1 ⁇ M.
  • Test compound stock and solution preparation Compounds prepared daily as stocks at 10 mM in 100% DMSO; Pipetting solution: 45 ⁇ M or serial dilutions thereof; pipette 20 ⁇ L into 140 ⁇ L volume in well for final well concentration: 1 ⁇ M or 10-fold dilutions thereof.
  • High potassium (depolarization) solution Buffer C with 240 mM K + added; pipette 80 ⁇ L into 160 ⁇ L volume in well for final well concentration of 80 mM K + .
  • Fluorescent dye solution preparation A calcium indicator dye, Fluo-4 acetylmethylester (Fluo 4- AM; Cat. # F- 124201; Molecular Probes, Eugene, OR) was used to measure changes in intracellular free calcium with FLIPR. 1 mM Fluo-4 AM stock solution was made by dissolution in DMSO. This stock was then diluted to 4.6 ⁇ M with Buffer B (Fluo-4 AM working solution).
  • Cell loading procedure Plates containing cells were washed with Buffer A using an automated cell washer (Model #: 5161552, Labsystems Oy, Helsinki, Finland) with controls set to the following parameters: cell height: C/D; cell pulse: 4/5, washes: 3; volume: 5; DRY position setting. These settings resulted in a 70 ⁇ L residual depth of buffer over cells in each well. 100 ⁇ L of the Fluo-4 AM working solution was then added to each well resulting in a final Fluo-4 AM concentration of 2.7 ⁇ M Cells were incubated in this solution at 37 °C for 1- 1.5 h.
  • FLIPR hardware settings Laser power was set to about 0.3 watts. Excitation wavelength was set to a 488 nm peak, and the emission wavelength to 540 nm. Camera aperture was set to 2. All experiments were conducted at room temperature (20-22 °C). . Plate layout - reference signals: Certain wells on each plate were allocated to standards to determine minimum and maximum specific fluorescent signal against which inhibitory effects of compounds were normalized.
  • the reference standards were distributed at plate locations including edge and interior wells Maximum signal (N-channel + non-specific): 12 wells were incubated in nitrendipine (1 ⁇ M) solution and 80 mM K* added to determine maximal Ca 2+ increase mediated by N-channels + non-specific (non-L-, non-N-channel mediated fluorescence increase). The coefficient of variation amongst these wells for the K + -evoked peak increase in fluorescence units was typically less than 12%.
  • ⁇ -channel reference small molecule A compound that had been characterized extensively with respect to ⁇ -channel inhibitory activity in both FLIPR and patch clamp electrophysiology was included on each plate in triplicate at 1 ⁇ M (near IC 50 ) to establish a reference point.
  • Test compounds 5 test compounds were evaluated for potency on each plate. Each compound was tested at 5 increasing concentrations spanning half-log units and typically reaching a maximal concentration of 10 ⁇ M. Each concentration was tested in triplicate wells.
  • the FLIPR protocol was configured as three solution addition/sampling sequences (see below). Conotoxin (1 ⁇ M final cone.) was added to appropriate wells prior to placing the plate in the FLIPR instrument. Wells initially contained a total solution volume of 100 ⁇ l, and after all three solution additions contained 240 ⁇ l. The active mixing (by the pipette) option was not used in any sequence.
  • Nitrendipine addition sequence 28 s total duration with fluorescence signal sampling at 1 Hz for 2 s, followed by addition of 20 ⁇ L nitrendipine standard solution at 10 ⁇ L/s, followed by sampling at 0.5 Hz for 24 s. •
  • Test compound addition sequence 64 s total duration with sampling at 0.5 Hz for 4 sec, test solution addition of 40 ⁇ L at 20 ⁇ L/s, followed by sampling at 0.2 Hz for 60 s.
  • FLIPR software Prior to export, the data was normalized within the FLIPR software module for two effects.
  • Baseline correction The baseline was corrected by "zeroing" at sample # 57 (immediately prior to KCl addition). This normalization served to correct the y axis offset of the fluorescent trace from each well so that all traces had a common point just prior to onset of the relevant evoked fluorescent increase.
  • Spatial uniformity correction factor The data was normalized by a procedure which calculates a mean over the plate of fluorescent units from the first sample, and then multiplies the data from each well by a scalar that adjusts the value of the first sample to this average value, thus normalizing for differences in absolute baseline fluorescence amongst the wells caused by differences in cell densities or dye loading.
  • the methods described below provided a reliable FLIPR-based readout of the efficacy and potency with which test compounds inhibited calcium flux through the L-type calcium channel expressed natively in a human-derived neuroblastoma cell line, SK-N-SH.
  • the degree to which a given compound concentration inhibited the L-channel was determined by comparing the amplitude of peak calcium increase to an 80 mM K + stimulus in the test well to the peak increase in wells without compound
  • the assay was validated by obtaining 5-point concentration-response curves and thereby determining ICso values for the reference L- channel blockers, nitrendipine (30 nM), nifedipine and verapamil. These values were compatible with the known literature values for these agents to block Ca 2+ flux through the L- channel.
  • SK-N-SH derived from human neuroblastoma cells
  • ATCC product # HTB-11 An immortalized cell line, SK-N-SH, derived from human neuroblastoma cells (ATCC product # HTB-11) was used for all experiments.
  • Cells were grown in T75 flasks containing Eagle's minimum essential medium (MEM) w/ Earle's salts, with 0.1 mM non-essential amino acids, 1.0 mM Na pyruvate and 10% fetal bovine serum (FBS; Cat. # SLM-034-B, Specialty Media). Cells were grown to 100% confluency (by visual microscopic estimation) before sub-culture.
  • MEM Eagle's minimum essential medium
  • FBS fetal bovine serum
  • Cells were sub-cultured at a ratio of 1:3 by first rinsing with 3 mL PBS, replacing the PBS with PBS containing 0.25% trypsin until the cells detached from the surface. 1 mL of the resulting suspension was then added to a new flask containing 10 mL fresh media. Cells were then incubated (37 °C, 5% CO 2 ), and media was exchanged about 3 days after subculturing.
  • Cells used for experiments were at the 100% confluency growth stage. Each flask provided enough cells for three 96-well plates. Cells were detached from the flask by addition of 0.25% trypsin, as described for the sub-culturing protocol. Once detached, 7 mL fresh media was added to the flask, and the solution triturated gently. An additional 20 mL media was then added, and 100 ⁇ L of this final cell suspension was then added to each well of a 96- well plate. Before use in experiments the plates were incubated at 37 °C in 5% CO 2 until cells reached 100% confluence (1-2 days). C. Experimental procedures:
  • composition of solutions, hardware settings, plate layout, structure of the FLEPR protocol, and analytical settings and procedures were identical to those described herein for the N-channel assays with the following differences as regards Plate layout and reference signals.
  • N-channel patch clamp electrophysiology 6 wells were incubated in nitrendipine (1 ⁇ M), followed by 80 mM K + added to determine background Ca 2+ with all L-channels pharmacologically occluded. The peak non-specific signal component was typically less than 15% of the maximum signal peak amplitude.
  • L-channel reference small molecule Nitrendipine was included in triplicate wells on each plate at 30 nM (near IC5 0 ) for a reference readout. III. N-channel patch clamp electrophysiology.
  • N-type current were recorded from both neuronally differentiated IMR-32 cells, and native neurons freshly dissociated from superior cervical ganglia of early postnatal rats. Each day, currents in both cell types were confirmed as N-currents showing that greater than 90% of the total inward current during depolarizing steps was blocked by a supramaximal concentration (3 mM) of w- conotoxin MNIIA. Additionally, the potency of w-conotoxin MNIIA was periodically determined to be about 3 nM (IC 50 ), a value consistent with that reported in the literature. Results for a subset of compounds tested in both cell types did not differ significantly, thus data are considered as one data set unless otherwise specified.
  • IMR-32 cell culture and differentiation
  • IMR32 cells were cultured and neuronally differentiated using procedures identical to those described for the FLIPR ⁇ -channel assay except that for differentiation cells were plated in 35 mm plexiglass culture dishes, rather than 96-well plates.
  • SCG superior cervical ganglion
  • rat pups 7-10 day old rat pups were euthanized in a chamber containing a high CO 2 atmosphere.
  • SCG were surgically isolated, removed and placed in ice cold Hanks balance salt solution (HBSS).
  • HBSS Hanks balance salt solution
  • SCG's were desheathed, cut open and placed in a solution of HBSS containing 20 U/mL papain (37 °C) for 15 min.
  • the papain solution was then exchanged for HBSS (37 °C) containing 16 mg/mL dispase and 400 U/mL collagenase for 40 min with gentle trituration of tissue every 15 min.
  • Cells were then recovered by centrifugation and stored in L-l 5 medium at 4 °C for use on the same day.
  • a drop of cell containing solution was placed on a poly-L-lysine coated 35 mm plexiglass culture dish, and cells allowed to adhere for several minutes.
  • An Axopatch IB amplifier (Axon Instruments, Foster City, CA) was used to obtain current signals and this was connected to a personal computer by either a TL-1 (Scientific Solutions, Solon, OH) or Digidata 1200 (Axon Instr.) interface.
  • the current signal was balanced to zero with the pipette immersed in the bath just prior to forming a seal on the neuron. Seal resistance ranged from 1 to greater than 10 G ⁇ . Series resistance was usually less than 10 M ⁇ , and was not compensated electronically. Digitized data acquisition and voltage step protocols were accomplished with pClamp 6.0 software (Axon Instr). Data were low-pass filtered at less than one-half the digital sampling rate prior to digitizing.
  • Test compounds were prepared as 10 mM stock solutions in DMSO, and appropriate volumes of these stock solutions dissolved into extracellular buffer to yield the desired concentrations. Solutions containing drugs/compounds were applied focally from any of six linearly arranged glass-lined tubes (200 mm o.d., Hewlett Packard, Wilmington, DE) positioned ⁇ 100 mm from the recorded neuron. Each solution was released from the desired tube by an electronically controlled solenoid valve system (BME Systems, Baltimore, MD). This system achieved rapid ( ⁇ 100 ms) equilibration of drug solution in the extracellular phase without perturbing the recording characteristics.
  • BME Systems electronically controlled solenoid valve system
  • Compounds of the invention generally had a binding affinity, expressed as the IC5 0 ( ⁇ M), for the N-type calcium channel, as measured by the FLIPR assay, of about 10 ⁇ M or less.
  • IC5 0 ⁇ M
  • the compounds of Examples 4, 66, 74 and 75 respectively have IC 50 's of 3.57, 2.37, 3.56 and 10.54 ⁇ M. IV. Formalin test.
  • the Formalin test assesses the inhibitory effects of orally administered N-type calcium channel antagonists on formalin-induced nocifensive behaviours in rats.
  • the formalin test is a well established pain test (Dubuisson and Dennis, 1977; Wheeler- Aceto et al, 1990; Coderre et al, 1993). This test consists of two distinct phases of formalin-induced behaviour. The first phase response, occurring between 0 to 5 minutes, is caused by acute nociception to the noxious chemical (formalin) injected into the paw. This is followed by a quiescent period of between 5 to 15 min post injection. A second phase response, occurring after 15 minutes and lasting up to 60 minutes, is caused by sensitisation of the central neurons in the dorsal horn. Central sensitisation augments the noxious afferent input and a stronger pain barrage is transmitted into the brain. Inhibition of the second phase response is indicative of a central mechanism of drug action.
  • the procedure for the formalin test is as follows: male rats are placed in a plexiglass chamber and observed for 30-45 min. to observe their baseline activity. Multiple groups of animals are pretreated with either vehicle or different doses of a test compound. Animals are dosed with the drug of interest either 40 min., if by the intraperitoneal route, or 90 min., if by the oral route, prior to injection of formalin into a hind paw . (under the dorsal skin; 0.05 mL of sterile 5% formalin). The number of paw flinches and licks during first phase (0-5 min.) and second phase (20-35 min.) are scored and recorded.
  • Flinch and lick responses are calculated as percentage of inhibition compared with the mean score of a saline control group.
  • Drug potencies are expressed as the dose which causes 50% of the maximum inhibitory effect ("ID 0 "). Student t-tests are used for statistical analysis to determine the significance of drug effects. Compounds are Considered active based on their ability to inhibit the flinch response. V. Chronic Constrictive Injury test.
  • CO Chronic Constrictive Pain
  • Neuropathic Pain Model assesses neuropathic pain associated with nerve injuries that can arise directly from trauma and compression, or indirectly from diseases ranging from infection to cancer, metabolic conditions, toxins, nutritional deficiencies, immunological dysfunction and musculoskeletal changes.
  • CCI Chronic Constrictive Injury
  • a unilateral peripheral neuropathy is produced in rats by partial nerve ligation.
  • Sprague-Dawley rats 250-350 g are anesthetized with sodium pentobarbital and the common sciatic nerve is exposed at the level of the mid-thigh by blunt dissection through the biceps femoris.
  • a section of nerve (about 7 mm), proximal to the sciatic trifurcation, is exposed and ligated 4 times with chromic gut suture.
  • the suture is tied with about 1 mm spacing between ligatures. The incision is closed in layers and the animals are allowed to recover.
  • Thermal hyperalgesia is measured using the paw- withdrawal test (Hargreaves et al, 1988).
  • Nerve compression due to the partial nerve ligation causes shorter latencies for paw withdrawal compared to the latency of paw withdrawal of paws of normal or sham operated legs.
  • Animals are habituated on an elevated glass floor.
  • a radiant heat source is aimed at the mid-plantar hindpaw (sciatic nerve territory) through the glass floor with a 20 second cut-off used to prevent injury to the skin.
  • Latencies for the withdrawal reflex in both paws are recorded.
  • Response to test compounds are evaluated at different times following oral administration to determine onset and duration of drug effect. Dose response studies are conducted with multiple groups of CCI rats dosed orally with either vehicle or the test compound for 5 days. Paw withdrawal latencies are measured each day prior to the first daily dose.
  • Method A Certain intermediates of exemplary compounds disclosed herein, see Table 1 , were prepared in a manner analogous to this method which describes the preparation of the quinoline intermediate, 2-(4-cyclohexylphenyl)-4,6-quinolinediamine, of Example 58.
  • the reaction pot was cooled, placed in a - 40 °C freezer and crystals were allowed to form for 24 hrs. Crystals were collected by vacuum filtration and solids washed with cold ethanol. The product was then dried in a vacuum oven to give 73.8 g (98%) of the desired enamine.
  • N-r2-(4-CyclohexylphenylV4-hydro ⁇ y-quinolin-6-yll-acetamide 1.2 L of Dowtherm A was charged into a 2 L three neck round bottom flask equipped with a condenser, magnetic stirrer, thermocouple, heating mantle with a variable voltage controller, and a nitrogen inlet.
  • the solvent was heated to 250 °C and 3-(4- acetylaminophenylamino)-3-(4-cyclohexylphenyl)-acrylic acid butyl ester 48 g (0.11 moles) was cautiously added in small portions. As portions were added gas was evolved and foaming occurred. Crystals of product began to form and adhere to the sides of the vessel.
  • N-F2-r4-CvclohexylphenylV4-methoxy-quinolin-6-yll-acetamide N-[2-(4-Cyclohexylphenyl)-4-hydroxy-quinolin-6-yl]-acetamide 35.7 g ( 0.099 moles) was placed in a 500 mL three neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet with 250 mL of toluene. The material was suspended by stirring and 20.6 mL (0.21 moles) of dimethyl sulfate was added. The suspension was then heated with a silicone oil heating bath, to gentle reflux for 18 hr.
  • N-r4-Amino-2-(4-cvclohexylphenyl -quinolin-6-vn-acetamide (35 g) was placed in a 500 mL three neck round bottom flask equipped with a mechanical stirrer and condenser, nitrogen inlet and gas outlet with 250 g of ammonium acetate. The stirred solid suspension was then heated to 115 °C. Ammonia was evolved and the material fused and dissolved in the acetic acid that formed over time. The temperature was slowly raised to 140 °C over 1 hr.
  • This compound was prepared from m-fiuoro acetophenone, in a manner analogous to the preparation of 3-(4-cyclohexylphenyl)-3-oxo-propionic acid ethyl ester (Method A), except that the product was purified by vacuum distillation (bp 114-117 °C at 0.8-0.9 mmHg) in 91% yield.
  • the reaction mixture was decanted while hot from a small amount of solids and chilled to -15 °C for 48 hours Crystalline solids were collected by vacuum filtration. The crystals were washed with 0.2 L of cold ethanol and two 0.2 L portions of hexanes and vacuum dried at 50 °C overnight to yield 35.8 grams (20.8% yield) of the title compound.
  • 6-Nitro-2-(3-fluorophenyl)-quinolin-4-ol 5.2 g (16.3 mmoles) was placed in a 500 mL three neck round bottom flask equipped with a condenser, magnetic stirrer and nitrogen inlet. To this was added 15.2 mL ( 25.0 g , 163 mmoles , 10 eqiv.) of phosphorus oxychloride with stirring. The mixture was then heated to 110 °C for 4 hr. At the end of this time the reaction was cooled to room temperature and water was cautiously added dropwise until all of the
  • 6-Nitro-4-chloro-2-(3-fluorophenyl)-quinoline 3.2 g (9.50 mmoles) was placed in a 250 mL three neck round bottom flask equipped with a condenser, magnetic stirrer, silicone oil heating bath, nitrogen inlet and gas outlet. To this was added 75 mL of N-methyl pyrrolidinone then 6.0 g ( 95 mmoles, 10 equiv.) of sodium azide. The mixture was stirred and warmed to 60 °C for 18 hr. After this time the mixture was cooled, poured into a 1 L separatory funnel containing 500 mL water and 250 mL of ethyl acetate.
  • 6-Nitro-4-azido-2-(3-fluorophenyl)-quinoline was placed in a 500 mL three neck flask equipped with a condenser, magnetic stirrer, nitrogen inlet gas outlet and a silicone oil heating bath and suspended in 250 mL of ethyl acetate and 50 mL of ethanol.
  • the mixture was stirred, heated to reflux, 20 g (89 mmoles, 6 equiv.) of stannous chloride dihydrate cautiously added portionwise over 40 min, and the mixture was heated for an additional 2 hr. At the end of this time, the mixture was cooled and poured into 500 mL of water. The pH was cautiously adjusted to 9.0 and the solution filtered.
  • a sodium hydride dispersion in mineral oil 160.0 grams (60%, 4.0 moles) was placed in a 12 L round bottom flask equipped with mechanical stirrer, thermometer, addition funnel and nitrogen inlet. The flask was cooled with an ice bath and 3.5 L of dry THF added with stirring, while maintaining the temperature below 20 °C.
  • To the suspension of stirred sodium hydride was added 376.4 grams (4.0 moles) of z ' so-butanol dissolved in 0.3 L of THF. The addition was carried out over about 2 hrs. at such a rate so as to maintain the temperature below 10 °C. The mixture was then allowed to warm to room temperature and stired for 1 hour.
  • a 60%-in-oil dispersion of sodium hydride 21.7 g (0.543 moles), was placed in a three-neck 2 L round-bottom flask equipped with an addition funnel, nitrogen inlet, magnetic stirrer, heating mantle, thermocouple and condenser with dry hexane (1 L). The resulting suspension was stirred for 15 minutes, stirring was halted and the solids were allowed to settle. The clear supernatant containing the hexane and dissolved oil was then removed via a cannula. Diethyl carbonate (1 L) was added and the suspension was heated to 120 °C.
  • 3-(4-Nitrophenylamino)-3-G-fluorophenylVacrylic acid butyl ester 3-(3-Fluorophenyl)-3-oxo-propionic acid ethyl ester, 106.3 grams (0.506 moles), 4- nitro-aniline, 63.0 grams (0.456 moles), and 4-nitro-aniline hydrochloride 4.0 grams (0.023 moles) were placed in a dry 2 L round-bottom flask. To the mixture was added 1.3 L of n- butanol, the flask was fitted with a Soxhlet extractor (cup volume of 0.3 L), condenser and nitrogen inlet.
  • Soxhlet extractor cup volume of 0.3 L
  • the column was eluted with 4.0 L of 1 : 1 methylene chloride to hexane; 9.0 L of 2: 1 methylene chloride to hexane; and 2.0 L of methylene chloride. Fractions of 0.5 L were collected and those containing the desired product combined to yield 41.7 grams (24.3%)of bright yellow solid. The combined yield was 45.1%.
  • N-r6-Nitro-2-( ' 3-fluorophenyl -4-quinolinyll-N,N-dimethylamine 6-Nitro-4-chloro-2-(3-fluoro-phenyl)-quinoline, 20 g (59.4 mmoles)
  • 6-Nitro-4-chloro-2-(3-fluoro-phenyl)-quinoline 20 g (59.4 mmoles)
  • the material was dissolved in 150 mL of N-methyl pyrrolidinone, stirred and 250 mL of a 40% aq. solution of dimethylamine was added. The mixture was then warmed to 60 °C for 48 hrs.
  • N-r2-( ' 3-FluorophenylV6-amino-4-quinolinyl]-N.N-dimethylamine N-[6-Nitro-2-(3-fluorophenyl)-4-quinolinyl]-N,N-dimethylamine with 150 mg of a catalyst consisting of 5% palladium on calcium carbonate support was placed in a 500 mL Parr shaker bottle. To this was added 150 mL of ethanol, followed by application of a 50 psi . hydrogen atmosphere. The mixture was shaken for 18 hr and the hydrogen atmosphere then replaced by nitrogen. The catalyst was removed by filtration and the solution concentrated.
  • Exemplary compounds disclosed herein, see Table 1, were prepared in a manner analogous to the following method which describes the preparation of N6-[2-amino-6-(4- fluorophenyl)-pyrimidin-4-yl]-2-phenyl-quinoline-4,6-diamine, the compound of Example 5.
  • 2-Phenyl-quinoline-4,6-diamine, 0.5 grams (2.12 mmole) and 4-chloro-6-(4- fluorophenyl)pyrimidin-2-amine, 0.83 grams (4.25 mmole) were weighed directly into a reaction flask and 10 mL of dry N-methyl-2-pyrolidinone and 2 drops of concentrated hydrochloric acid was then added to the flask.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des composés utiles pour le traitement de la douleur et conformes au diagramme structurel suivant, où R1, R2 et R3 représentent respectivement l'un quelconque des groupes définis dans la description. L'invention concerne également les compositions pharmaceutiques et les procédés de traitement utilisant ces composés.
PCT/SE2001/002388 2000-11-06 2001-10-31 Antagonistes des canaux calciques de type n pour le traitement de la douleur WO2002036586A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP01981239A EP1339706B1 (fr) 2000-11-06 2001-10-31 Antagonistes des canaux calciques de type n pour le traitement de la douleur
AU2002212894A AU2002212894A1 (en) 2000-11-06 2001-10-31 N-type calcium channel antagonists for the treatment of pain
JP2002539345A JP2004513125A (ja) 2000-11-06 2001-10-31 疼痛治療のためのｎ−型カルシウムチャンネル拮抗薬
US10/415,785 US6815447B2 (en) 2000-11-06 2001-10-31 N-type calcium channel antagonists for the treatment of pain
DE60118956T DE60118956T2 (de) 2000-11-06 2001-10-31 Calciumkanalantagonisten vom n-typ zur behandlung von schmerzen

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE0004053-5 2000-11-06
SE0004053A SE0004053D0 (sv) 2000-11-06 2000-11-06 N-type calcium channel antagonists for the treatment of pain

Publications (1)

Publication Number Publication Date
WO2002036586A1 true WO2002036586A1 (fr) 2002-05-10

Family

ID=20281713

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/SE2001/002388 WO2002036586A1 (fr) 2000-11-06 2001-10-31 Antagonistes des canaux calciques de type n pour le traitement de la douleur

Country Status (9)

Country Link
US (1) US6815447B2 (fr)
EP (1) EP1339706B1 (fr)
JP (1) JP2004513125A (fr)
AT (1) ATE323693T1 (fr)
AU (1) AU2002212894A1 (fr)
DE (1) DE60118956T2 (fr)
ES (1) ES2261496T3 (fr)
SE (1) SE0004053D0 (fr)
WO (1) WO2002036586A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003099284A1 (fr) * 2002-05-22 2003-12-04 Amgen Inc. Amino-pyridine, derives de pyridine et de pyridazine utilises comme ligands de recepteur vanilloide permettant de traiter une douleur
WO2004014871A1 (fr) 2002-08-08 2004-02-19 Amgen Inc. Ligands de recepteur vanilloide et leur utilisation dans des traitements
EP1691812A1 (fr) * 2003-11-20 2006-08-23 Children's Hospital Medical Center Inhibiteurs de gtpase et procedes d'utilisation correspondants
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7419984B2 (en) * 2002-10-17 2008-09-02 Cell Therapeutics, Inc. Pyrimidines and uses thereof
US7423148B2 (en) 2002-11-21 2008-09-09 Chiron Corporation Small molecule PI 3-kinase inhibitors and methods of their use
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040259866A1 (en) * 1998-06-30 2004-12-23 Snutch Terrance P. Calcium channel blockers comprising two benzhydril moieties
CA2603926A1 (fr) * 2005-04-08 2006-10-12 Neuromed Pharmaceuticals Ltd. Therapie de combinaison qui comprend un agent bloquant les canaux calciques de type n pour le soulagement de la douleur
WO2007133481A2 (fr) * 2006-05-11 2007-11-22 Neuromed Pharmaceuticals Ltd. Méthode d'augmentation de la biodisponibilité de composés contenant de la benzhydrylpipérazine
CN102933079B (zh) 2010-03-04 2016-02-17 默沙东公司 儿茶酚-o-甲基转移酶抑制剂及其在治疗精神障碍中的用途
MX336711B (es) 2010-03-04 2016-01-28 Merck Sharp & Dohme Inhibidores de catecol o-metil transferasa y su uso en el tratamiento de transtornos psicoticos.
BR112012021652A2 (pt) 2010-03-04 2016-06-21 Merck Sharp & Dohme composto, uso do mesmo, e, composição farmacêutica
US8409560B2 (en) 2011-03-08 2013-04-02 Zalicus Pharmaceuticals Ltd. Solid dispersion formulations and methods of use thereof
JP2014507424A (ja) 2011-03-08 2014-03-27 ザリカス ファーマスーティカルズ リミテッド 固体分散物製剤およびその使用方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB794043A (en) * 1955-06-03 1958-04-30 Ici Ltd New quinoline derivatives
WO1999048492A1 (fr) * 1998-03-26 1999-09-30 Japan Tobacco Inc. Derives d'amide et antagonistes de nociceptine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB794043A (en) * 1955-06-03 1958-04-30 Ici Ltd New quinoline derivatives
WO1999048492A1 (fr) * 1998-03-26 1999-09-30 Japan Tobacco Inc. Derives d'amide et antagonistes de nociceptine

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7396831B2 (en) 2002-05-22 2008-07-08 Amgen Inc. Vanilloid receptor ligands and their use in treatments
AU2003247425B8 (en) * 2002-05-22 2003-12-12 Amgen Inc. Amino-pyridine, -pyridine and pyridazine derivatives for use as vanilloid receptor ligands for the treatment of pain
US7053088B2 (en) 2002-05-22 2006-05-30 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7524874B2 (en) 2002-05-22 2009-04-28 Amgen Inc. Vanilloid receptor ligands and their use in treatments
AU2003247425B2 (en) * 2002-05-22 2007-03-08 Amgen Inc. Amino-pyridine, -pyridine and pyridazine derivatives for use as vanilloid receptor ligands for the treatment of pain
WO2003099284A1 (fr) * 2002-05-22 2003-12-04 Amgen Inc. Amino-pyridine, derives de pyridine et de pyridazine utilises comme ligands de recepteur vanilloide permettant de traiter une douleur
WO2004014871A1 (fr) 2002-08-08 2004-02-19 Amgen Inc. Ligands de recepteur vanilloide et leur utilisation dans des traitements
JP2006504670A (ja) * 2002-08-08 2006-02-09 アムジエン・インコーポレーテツド バニロイド受容体リガンドおよびそれの治療での使用
US7144888B2 (en) 2002-08-08 2006-12-05 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7148221B2 (en) 2002-08-08 2006-12-12 Amgen Inc. Vanilloid receptor ligands and their use in treatments
EA010380B1 (ru) * 2002-08-08 2008-08-29 Амген Инк. Лиганды ванилоидных рецепторов
US7332511B2 (en) 2002-08-08 2008-02-19 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7419984B2 (en) * 2002-10-17 2008-09-02 Cell Therapeutics, Inc. Pyrimidines and uses thereof
US7423148B2 (en) 2002-11-21 2008-09-09 Chiron Corporation Small molecule PI 3-kinase inhibitors and methods of their use
US7767669B2 (en) 2002-11-21 2010-08-03 Novartis Ag Small molecule PI 3-kinase inhibitors and methods of their use
JP2007512363A (ja) * 2003-11-20 2007-05-17 チルドレンズ ホスピタル メディカル センター Ｇｔｐアーゼ阻害剤および使用方法
EP1691812A1 (fr) * 2003-11-20 2006-08-23 Children's Hospital Medical Center Inhibiteurs de gtpase et procedes d'utilisation correspondants
EP1691812A4 (fr) * 2003-11-20 2010-01-13 Childrens Hosp Medical Center Inhibiteurs de gtpase et procedes d'utilisation correspondants
JP4691041B2 (ja) * 2003-11-20 2011-06-01 チルドレンズ ホスピタル メディカル センター Ｇｔｐアーゼ阻害剤および使用方法
US7301022B2 (en) 2005-02-15 2007-11-27 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US8217035B2 (en) 2006-01-20 2012-07-10 Novartis Ag Pyrimidine derivatives used as PI-3-kinase inhibitors
US8563549B2 (en) 2006-01-20 2013-10-22 Novartis Ag Pyrimidine derivatives used as PI-3 kinase inhibitors
US8173647B2 (en) 2007-02-06 2012-05-08 Gordana Atallah PI 3-kinase inhibitors and methods of their use
US8957068B2 (en) 2011-09-27 2015-02-17 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US8865894B2 (en) 2012-02-24 2014-10-21 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US9458177B2 (en) 2012-02-24 2016-10-04 Novartis Ag Oxazolidin-2-one compounds and uses thereof
US9296733B2 (en) 2012-11-12 2016-03-29 Novartis Ag Oxazolidin-2-one-pyrimidine derivative and use thereof for the treatment of conditions, diseases and disorders dependent upon PI3 kinases
US10202371B2 (en) 2012-11-12 2019-02-12 Novartis Ag Oxazolidin-2-one-pyrimidine derivatives and the use thereof as phosphatidylinositol-3-kinase inhibitors
US9434719B2 (en) 2013-03-14 2016-09-06 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US9688672B2 (en) 2013-03-14 2017-06-27 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH
US10112931B2 (en) 2013-03-14 2018-10-30 Novartis Ag 3-pyrimidin-4-yl-oxazolidin-2-ones as inhibitors of mutant IDH

Also Published As

Publication number Publication date
ES2261496T3 (es) 2006-11-16
EP1339706B1 (fr) 2006-04-19
US20040058945A1 (en) 2004-03-25
EP1339706A1 (fr) 2003-09-03
AU2002212894A1 (en) 2002-05-15
DE60118956T2 (de) 2007-03-15
SE0004053D0 (sv) 2000-11-06
DE60118956D1 (de) 2006-05-24
ATE323693T1 (de) 2006-05-15
US6815447B2 (en) 2004-11-09
JP2004513125A (ja) 2004-04-30

Similar Documents

Publication Publication Date Title
US7348340B2 (en) N-type calcium channel antagonists for the treatment of pain
US6815447B2 (en) N-type calcium channel antagonists for the treatment of pain
US5776935A (en) Pyrido-phtalazin diones and their use against neurological disorders associated with excitotoxicity and malfunctioning of glutamatergic neurotransmission
PT2125776T (pt) Compostos espiro substituídos como inibidores da angiogénese
US7153865B2 (en) N-type calcium channel antagonists for the treatment of pain
RU2595894C2 (ru) Замещенные 2-окси-хинолин-3-карбоксамиды в качестве модуляторов kcnq2/3
CA2133620A1 (fr) Derives d'aminoquinoleine
US6841680B2 (en) N-type calcium channel antagonists for the treatment of pain
US6906193B2 (en) N-type calcium channel antagonists for the treatment of pain
US7060834B2 (en) N-type calcium channel antagonists for the treatment of pain
AU671814B2 (en) Nitroquinolone derivatives as NMDA antagonists
JP7191045B2 (ja) 化合物
CN111108083A (zh) 氨基亚甲基环己烷1,3-二酮化合物的用途

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 2002539345

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: 2001981239

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 2001981239

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWE Wipo information: entry into national phase

Ref document number: 10415785

Country of ref document: US

WWG Wipo information: grant in national office

Ref document number: 2001981239

Country of ref document: EP